The clinical traits of acute pancreatitis in aging patients: a retrospective analysis of 473 cases

The incidence of acute pancreatitis in aging patients has increasing in recent years. Controversial results about clinical outcomes of acute pancreatitis in aging patients were reported in different literature. The aim of our study was to compare the clinical outcomes of AP in aging patients between 60-79 years old and over 80 years old. 80 patients aged ≥ 80 years old(oldest group) were compared to 393 patients aged 60 to 79 years old(older group). The clinical course, biochemical, radiological data were enrolled. The primary endpoint was to compare the death rate, intensive care unit admission rate and in-hospital length of stay(LOS). The secondary endpoint was operative treatment and the complications of AP. AST. nitrogen Glucose retrograde pseudocyst=PPC. Walled-off necrosis=WON. Acute peripancreatic fluid collection=APFC. Acute necrosis collection=ANC. Percutaneous drainage=PCD. Hypertriglyceridemia=HTG. Odds ratio=OR. Computed tomographic=CT.


Background
In Europe, the improvement of medical and health environment resulted an increase of 2.4% aging people over 65 years in the past decade. More importantly, they predicted that aging people aged over 80 years old is expected to reach the 12.7% of all people in 2080 as compared to the 5.5% in 2007 [1]. With the aging of world population trends in the intensification of the aging phenomenon has become a major strategic issue and an increasing number of aging patients suffered to acute pancreatitis(AP) [2][3][4].
AP is a potentially fatal clinical disease which is characterized by edema, hemorrhage and necrosis [5][6][7]. The clinical process of AP varies from a self-limiting acute inflammation to a clinically severe condition, potentially leading to life-threatening disease for the risk of multi-organ failure [8]. The death rate of AP is extremely different varying from 5% of mild acute pancreatitis(MAP) [9,10] up to 30% or more of severe acute pancreatitis(SAP) [11,12].
AP is a life-threating disease that is certificated by large numbers of researches. The frail population of aging people easily developed to severe condition as compared to younger patients after AP onset. Hence, it is necessary to figure out the outcome and the clinical traits of AP in the increasing part of aging population and recognized a useful medical and interventional treatment in this high risk category is crucial .
The diagnosis of AP in aging patients is more difficult for physician compared to the younger AP patients. The symptoms of aging patients were presented later and have nonspecific presentation in the development of the disease [13]. Furthermore, their great number of comorbidities rate may potentially result to severe consequences in such an 4 acute disease [14][15][16][17].
However, although age is an element influencing the procession of AP [18][19][20][21], its influence on the clinical traits in AP remained controversial. The reason probably due to the presence of only little studies surveyed the clinical traits of AP in aging population. A research reported that aging patients have a more severe course in elderly patients but the mortality rate is not increased [14]. Conversely, other studies proposed that age itself is an independent risk factor for intensive care unit (ICU) admission and mortality [19,22].
Actually, age is an vital component utilized in stratified the severity of the disease [8].
These inconsistent results of those research are probably due to the different age partitions to define aging patients by different countries and authors, thus making difficult to compare the clinical outcomes of AP aging patients. Hence, it is necessary to divided the aging patients to a heterogeneous cohort and then analyze the clinical outcomes of AP patients according to the different age subsets.
In our research, we decided to focus our attention on the subgroup of oldest patients group (≥ 80 years) and the older patients group (60-79 years) according to Chinese age standardization of rates. The aim of our study was to investigate the clinical traits of AP in oldest patients group and older patients group like incidence, clinical course, and mortality rate.

Patient data
The retrospective study enrolled all patients with AP from the AP database of the First Affiliated Hospital of Nanchang University, which was approved by the ethics committee (database approval number: 2011001). The study comprised 2148 patients recruited from the AP database from January 1, 2018 to December 31, 2019. Younger than 60 years of AP patients were excluded from the study, as were those more than 7d after AP onset and so on. We eventually enrolled 473 aging patients of AP in our study. The exclusion criterias were as listed in Fig. 1. Clinical data such as age, sex, history of smoking and drinking, Diabetes, hypertension, history of renal diseases, complications, the severity and etiology of AP during hospitalization, death, biomarkers of clinical tests, Length of stay in hospital after AP onset, intensive care unit(ICU)admission and body mass index (BMI) on admission and so on were recorded by us. BMI(kg/m2) was defined as weight in kilograms divided by height in square metres. Acute physiology and chronic health evaluation II (APACHE II) score, Bedside index for severity in acute pancreatitis score, Marshall and Glasgow score were calculated based on patient data.

Diagnosis and definition
The total population was divided into two groups called the older group and the oldest group. The older group was patients aged from 60 to 80 years old. The oldest group was AP patients aged over 80 years. The diagnosis of AP was based on the 2012 revised Atlanta classification criteria [23]. The 2012 revision of the Atlanta Acute Pancreatitis Diagnostic and Classification Criteria was used to classify the AP severity and etiology.
Organ failure was according to the modified Marshall Scoring System [23]. Pancreatic complications was diagnosed by Contrast-enhanced computed tomography (CECT) which indicated by diffuse enlargement of the pancreatic or peripancreatic volume, blurred edges, mild enhancement of the edema area after enhanced scanning, and no enhancement of necrotic areas [10,24]. The death regarded as death during hospitalization. The definition is shown in Supplementary Table 1 Creatinine(Cr)) were assessed in due consideration of the respective older group (60-79 years)and oldest group(≥ 80 years). Chronic pancreatitis or pancreatic cancer in our study were excluded from further assessment.

Statistical analysis
Categorical variables were statistically compared by the chi-square test at the univariate analysis. Mann-Whitney U test was used to continuous variables.
Categorical variables are presented as numbers and percentages, and continuous variables are presented as median and mean difference. 0.05 was regarded as the significance level. Variable significant at univariate and multivariate analysis of logistic regression model were used to distinguish independent factor of mortality, in-hospital length of stay(LOS) and ICU admission rate. Results were expressed as odds ratio (OR) with 95% confidence interval (CI). All data were analyzed by SPSS 24 R.

Results
From January 2018 to December 2019, a total of 2148 patients were admitted in the tertiary hospital, the first affiliated hospital of Nanchang university. Four hundred seventy-three aging AP patients were finally included after excluding unqualified patients of AP. The flow chart was listed in Fig. 1 score in oldest group (13.08 ± 3.50) is higher than older group (11.91 ± 3.74). There was significant different in the two groups(p = 0.01). Other scores were also listed in Table 2.
History of smoking and drinking, Chronic renal failure, hypertension, diabetes, severity of AP and incidence of complication were presented in Table 1 as baseline characteristics.
According to the biochemical values, there were no differences in the older group and oldest group including white blood cell (WBC), serum amylase, C-reactive protein(CRP) and so on as listed in Table 2.   Table 2 Comparison of the laboratory tests and score of AP patients in the older group and oldest group.  Various clinical symptoms were presented in AP patients. In our study, we found that abdominal pain was more frequently occurred in the older group than oldest group (241 patients (61.3%) vs. 37 patients (46.3%)). While the symptoms of diarrhea, jaundice, dyspnea were more often happened in oldest AP patients. While symptoms of vomiting emerged an approximately similar incidence in the older and oldest group (26 patients (6.6%) vs. 8 patients (10.0%)). Meanwhile, the symptoms of diarrhea, jaundice, dyspnea were always accompanying abdominal pain in aging AP patients. The details were listed in Table 1.
The main etiology of AP among the aging patients was biliary (81.2% in aging patients).
The similar incidence of the etiology of gallstones of AP were verified in the oldest group(71 patients (88.6%)) and older group(313 patients (79.6%)). Alcohol, hypertriglyceridemia, and other type of AP were also listed in Table 1.
According to the contrast-enhanced computerized tomography (CECT), Acute necrosis collection (ANC) was detected in 26(6.6%) patients of the older group as compared to 5(6.3%) patients of the oldest cohort. Acute peripancreatic fluid collection (APFC), a more common pancreatic complication, presented a large proportion of rate in the two aging group (108 and 15 in the older and oldest cohorts, respectively). Walled-off necrosis(WON) was found in 4 (1.3%) and 2 (2.5%) patients of the older group and oldest group,  ICU Admission (the Details Were Listed In Table 4) 14 length of stay(LOS) (The details were listed in Table 5)

Discussion
With an great increase of aging population all over the world and the prolongation of life span, a great number of age-associated acute and chronic diseases has been occurred. AP was one of the acute diseases and the incidence rate increases proportionally with the increasing age [25]. Data from an emergency departments(ED) presented that aging patients aged over 65 years old diagnosed with AP reached one-third of all patients [8].
Another register study reported that a six-fold increase in the incidence rate from AP patients aged 0-49 years to patients over 80 years during a decade [26].
Despite we have paid attention to the importance of clinical outcomes of the frailer portion of population of AP, but it is only a small part of researched with limited data and disputable results are present in those articles. A study from European published that the morbidity rate of AP aging patients aged ≥ 65 years was increased and especially among the aging patients ≥ 80 years [4]. However, Kim JE.el proposed that the clinical courses of AP between older and younger patients have not evidenced any significant difference [15].
The difference between those research probably due to the age bracket set by the different authors. Actually, based on those study, they mostly make a conclusion that aging patients generally developed to a more severe AP and age may regarded as a risk factor for the clinical outcomes. With the purpose of giving a more contribution to this still controversial issue, we compared the clinical outcomes of the aging AP patients divided into older group (60-79 years old) and oldest group (≥ 80 years old) who admitted to our pancreas centre in the first affiliated hospital of Nanchang university of China. Given the increase of life expectancy of aging patients in China, the cut-off chosen of age in our study will represent a large proportion of the aging patients in the near future.
In our retrospective study, we aimed at analyzing the age-associated clinical outcomes and assessed the risk factors of aging patients in the disease. Interestingly, our study figured out aging patients aged over 80 years old significantly influenced the mortality rate and length of hospitalization, while the ICU admission rate was similar to the older group.
With the clinical presentation of aging AP patients, more severe manifestations was found in the oldest group as compared to the older group in our study. The phenomenon has also been evidenced by previous research that increasing age was closely related to a more severe clinical course of AP[15- 18,27]. The underlying mechanism of the above condition is still debate. A view proposed in a literature that the increasing age was associated to the loss of protective proteins of AP which led an adverse clinical course in oldest patients of the disease [28]. Pre-existing comorbidities such as diabetes, chronic renal disease would influence the physiological functions of aging AP patients which causing a more severe inflammatory response reflected as primary clinical manifestation of the disease [13].
According to clinical experiences, the clinical assessment of aging patients is usually more harder than younger patients [29]. and it is verified in our research that the absence of typical symptoms in our aging patients was 28% in all enrolled patients. It reminds us that increased awareness in aging AP patients should be given, especially for the more severe 19 AP patients. In our study, we found that abnormal symptomatology was show in the aging AP patients. At this regard, a less frequent abdominal pain was evidenced in the oldest group rather than the older group which is in line with previous studies who report a decline of abdominal pain in aging patients over 80 years old. It may linked to a greater capacity to endure the pain and less feedbacks. In our study, we found that the abdominal pain was significant related to the ICU admission rate in aging patients for the first time.
While the clinical symptom was not associated to the death rate which was not in line with previous study presented that the death rate is closely related to the abdominal pain [13].
We speculated that the phenomenon evidenced in our research was attributed to the fully treatment experience for more severe aging AP patients in our hospital, which is one of the largest pancreas centre in China, leading a higher ICU admission rate and lower death rate.
Besides, an interesting phenomenon of the symptoms was evidenced in our study that dyspnea, jaundice and diarrhea presented more frequent in oldest patients as compared to older group (P < 0.05).The relation between AP and dyspnea symptoms in aging patients has been already reported [22]. While the other two symptoms of jaundice and diarrhea was not in line with previous research which reported that those symptoms was similar in older and oldest group. We suspected that age itself was the explanation regard to diversity of symptoms in aging people of AP. In addition, our study also surprised founds that the of symptom of jaundice is related to LOS which have not reported by other studies. The conditions reminder us that we should pay more attention to the symptoms of diarrhea, jaundice, dyspnea in the absence of abdominal pain of AP in aging patients in the future which bring lower death rate, ICU admission rate and shorter LOS.
A research have reported that lower BMI ranged 18.5 to 19.9 had a higher risk of death rate relative to those population with a BMI over 21.5[30]. Another study finds that BMI 20 less than 20.0 is associated with an increased risk of death, whereas a BMI ≥ 23.0 is not associated with higher death rate [31]. In our study, lower BMI (21.07 ± 3.18) was evidenced in oldest as group compared to older group(22.36 ± 2.89) and there were significant difference in the two group. Although the BMI is not the independent risk factor of death rate in our study, the BMI related age is associated to dying. One potential explanation for this may relate to energy and nutritional reserves. Malnutrition is verified a predictor of death and thin people with less energy and nutritional are less resistant to infection [32]. Hence, aging patients should take appropriate nutrition to increase their BMI to resist the disease.
Over expression of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-α was verified after AP onset as an already known proinflammatory status. The proinflammatory facilitates systemic symptoms, especially respiratory and renal injury as first manifestation of AP. In particular, IL-6, TNF-α and the alveolar macrophages were accumulated after the neutrophils activated in the lung, then develop a kind of second wave of inflammation causing the onset of respiratory symptoms as first expression [33].
According to the conditions, it is necessary to provide intensive care, guarantee an enough monitoring of cardiopulmonary and a more suitable electrolytes and fluid replacement for the aging patients after AP onset [8]. With this regard, we found that a higher rate of ICU admission in the oldest group compared to older group and age ≥ 80 years was an independent risk factors for ICU admission rate.
In regard to the etiology of AP, the most common cause of AP was biliary in aging patients which was much higher percentage in younger AP patients. But the proportion of biliary pancreatitis in the etiology of AP was no significant difference in older group and oldest group. The result was in line with previous researches that the higher incidence rate of gallstones-inducing AP was related to the increasing age [5]. In addition, we found that alcohol-induced AP and HTG-induced AP were less frequently encountered in aging patients. Previous study have been reported that alcoholic AP occurred more often in younger subjects [5]. While HTG, a common etiology of AP in China which accounts for 40% of all AP patients, have been decline to a small proportion of the etiology of AP. We speculated that the phenomenon of more frequent gallstone-induced AP in aging patients was associated to a more frequent disease of gallstones, with an much more thickening diameter of the common bile duct, which make aging patients more liable to the onset of biliary-induced AP [34,35]. Although a literature stated a more severe clinical course among the disease of biliary-induced AP [36], we did not discover the relationship between gallstones-induced pancreatitis and mortality, ICU admission, or LOS in the multivariate logistic analysis in our aging AP patients. It is in line with the hypothesis which has been confirmed that the worst clinical outcomes in the aging AP patients would be mainly explained by other risk factors rather than etiology [37].
Regarding to the operative treatment, ERCP was the most common operation performed in the aging patients in our study. A similar rate of operative treatment of ERCP has been verified between the two old group. The phenomenon is caused by the proportion of the  [16,41]. In addition, a lower death rate (7.1%) was evidenced in recent study in older patients over 65 years old [13]. The discrepancy of death rate in our research and others was associated to the early diagnosis and the different proportion of severity of the disease.

Study Limitations
Although the largest number of aging AP patients aged ≥ 80 years old in our hospital of china was enrolled in our study which focuses on the AP clinical course and we represented the common management of those patients, some limitations should be listed. Firstly, it is a retrospectively study contains potential biases in study design.
Secondly, it is not a multicentre study in different tertiary hospitals which presented the clinical traits in all aging AP patients in China.

Conclusion
Biliary pancreatitis is the main etiology of AP in aging patients especially aged ≥ 80 years old. There is a closely relationship between increasing age and death rate and LOS. In addition, more attention should be given to the clinical symptoms in this frailer portion of the population. Based on our finding of this study, we proposed that a more comprehensive and goal-directed attendant diagnostic procedures should be done to early detect the disease and improve the outcomes in aging patients. FundingThe study design and data collection were funded by the national natural science

Availability of data and materials:
The data enrolled and analyzed in our study are not publicly available due to appropriate protection of patient personal information but are available from the corresponding author on reasonable request. This study is a retrospective analysis, it did not include any human trial, and as such no informed consent from patients was needed. Figure 1 Flow